Study of Oral ONC201 in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma

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The goal of the first part is to find the highest tolerable dose of ONC201 that can be given to patients with relapsed or refractory MCL, DLBCL, and TLCL. Groups of subjects will receive increasing doses of ONC201 by mouth on day 1 of each 21 day cycle or on Day 1 of every week until there are side effects that are not tolerated or a maximum of 625 mg has been found to be tolerable.

As a result of new information, it has been decided that subjects in Arm A will continue receiving their dosing every 3 weeks. All other subjects will be dosed weekly.

The dose you receive may be too low to have an effect or so high it causes bad side effects.

In the second part of this study the highest dose of NC201 will be given to learn if ONC201 can help to control the disease.

Please note that this is the first time ONC201 will be given to human subjects.

Phase I starting dose of ONC201 125 mg taken orally Day 1 of every 21-day cycle (enrollment in Arm A stopped February 2016). After end-of-dosing visit, study staff will call participant every 3 months for 1 year.

Drug: ONC201

Phase I starting dose of ONC201: 125 mg taken by mouth taken Day 1 of every 21-day cycle (Arm A, closed to new enrollment February 2016) or once weekly (Arm B).

Phase I starting dose of ONC201 125 mg taken orally Day 1 of every week. Dose escalation will continue until MTD is reached for recommended Phase 2 Dose. After end-of-dosing visit, study staff will call participant every 3 months for 1 year.

Drug: ONC201

Phase I starting dose of ONC201: 125 mg taken by mouth taken Day 1 of every 21-day cycle (Arm A, closed to new enrollment February 2016) or once weekly (Arm B).

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Willing and able to participate in all study related procedures and therapy including swallowing capsules without difficulty.

Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test and must be willing to use acceptable methods of birth control during the study and for 90 days after the last dose of study treatment. Acceptable methods of birth control include condoms with birth control foam, birth control pills, implantable or injectable birth control, birth control patch, intrauterine device (IUD), or diaphragm with spermicidal gel. Male patients must use an effective barrier method of contraception (i.e. , condoms with birth control foam or diaphragm with spermicidal gel) during the study and for 90 days following the last dose of study treatment if sexually active with a female of childbearing potential. Contraception must be in place at least 2 weeks prior to initiating study treatment.

#9 cont. - * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Use of any standard/experimental anti-lymphoma drug therapy, including steroids (dexamethasone dose >/= 4 mg/day or prednisone >/= 20 mg/day), within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment. Hydroxyurea is permitted up to 24 hours before the first dose of study drug in patients with rapidly-proliferating disease.

Prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy. (Patients that require immunosuppressive therapy are not eligible within 60 days of therapy.)

History of human immunodeficiency virus (HIV) infection. Patients with active Hepatitis B infection (not including patients with prior Hepatitis B vaccination; or positive serum Hepatitis B antibody). Hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation. HIV screening is not required for this study.

Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to enrollment.

Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ONC201

Major surgery within 4 weeks of initiation of therapy.

The patient has a prior or concurrent malignancy that in the opinion of the investigator, presents a greater risk to the patient's health and survival, than of the MCL, within the subsequent 6 months at the time of consent. Investigator discretion is allowed.

Patients with New York Heart Association (NYHA) Class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree AV block type II, 3rd degree block, QT prolongation (QTc > 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light headedness and syncope. Patients with active atrial fibrillation will be excluded. The protocol excludes patients who have within the past year had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin equivalent vitamin K antagonist.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.